Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata -- SMART United States 2016-2017

Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata -- SMART United States 2016-2017

Accepted Manuscript Title: Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata – ...

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Accepted Manuscript Title: Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata – SMART United States 2016-2017 Author: Sibylle H. Lob Daryl J. Hoban Katherine Young Mary R. Motyl Daniel F. Sahm PII: DOI: Reference:

S2213-7165(19)30183-3 https://doi.org/doi:10.1016/j.jgar.2019.07.017 JGAR 995

To appear in: Received date: Revised date: Accepted date:

12 April 2019 24 June 2019 15 July 2019

Please cite this article as: Lob SH, Hoban DJ, Young K, Motyl MR, Sahm DF, Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata - SMART United States 2016-2017, Journal of Global Antimicrobial Resistance (2019), https://doi.org/10.1016/j.jgar.2019.07.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients

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in Different Risk Strata -- SMART United States 2016-2017

3 Sibylle H. Lob,a# Daryl J. Hoban,a Katherine Young,b Mary R. Motyl,b and Daniel F. Sahma

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International Health Management Associates, Inc., 2122 Palmer Drive, Schaumburg, IL, 60173, USA

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Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA

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The results of this report were presented in part at ASM Microbe 2018, Atlanta, GA, June 7-11, 2018

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Mailing address: International Health Management Associates, Inc., 2122 Palmer Drive, Schaumburg, IL,

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60173, USA. Phone: +1 (847) 303-5003. Fax: +1 (847) 303-5601.

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Address correspondence to Sibylle H. Lob, [email protected]

Authors’ email addresses:

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Sibylle H. Lob, [email protected]

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Daryl J. Hoban, [email protected]

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Katherine Young, [email protected]

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Mary R. Motyl, [email protected]

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Daniel F. Sahm, [email protected]

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Abstract

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Objectives: Infections caused by Pseudomonas aeruginosa are often difficult to treat. Knowledge of the

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risk of infection with resistant P. aeruginosa would allow more discriminatory prescribing of broad-

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spectrum antimicrobials. Using clinical isolates collected as part of the Study for Monitoring

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Antimicrobial Resistance Trends (SMART), we examined the activity of commonly used β-lactams,

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levofloxacin, and ceftolozane-tazobactam (C/T), an antipseudomonal cephalosporin/β-lactamase

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inhibitor approved in the United States and over 60 countries worldwide, against P. aeruginosa isolates

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from patients in different risk strata.

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Methods: In 2016-2017, 25 hospitals in the US each collected up to 250 consecutive gram-negative

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bacilli per year from respiratory tract (RTI), intraabdominal (IAI), and urinary tract (UTI) infections. MICs

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of 9,964 isolates (including 1,887 P. aeruginosa) were determined using CLSI broth microdilution and

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interpreted with CLSI breakpoints.

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Results: Susceptibility of all P. aeruginosa isolates combined was 94.7% to C/T and 76.8%, 77.0%,

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70.2%, and 69.0% to ceftazidime, meropenem, piperacillin-tazobactam, and levofloxacin, respectively.

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Susceptibility to the β-lactam comparators was 8-11 percentage points lower among ICU than non-ICU

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isolates, 7-11 points lower in isolates collected ≥48 hours than <48 hours post-admission, 1-5 points

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lower in patients <65 years of age than older patients, and 3-12 points lower in RTI than IAI and UTI

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isolates. C/T maintained activity against >90% of P. aeruginosa isolates in all risk strata and against 75-

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89% of isolates nonsusceptible to ceftazidime, meropenem, or piperacillin-tazobactam.

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Conclusions: C/T represents a promising new treatment option even in strata in which the risk of

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infection with β-lactam-nonsusceptible P. aeruginosa appeared higher.

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Keywords: Ceftolozane-Tazobactam; Pseudomonas aeruginosa; United States; surveillance;

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susceptibility 2 Page 2 of 21

1. Introduction

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Pseudomonas aeruginosa typically causes serious healthcare-associated infections, especially blood

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stream infections, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP), but

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has also been identified in 1.1-8.3% of patients with severe community-acquired pneumonia (CAP) [1,2].

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P. aeruginosa isolates have been reported to constitute 6-15% of gram-negative pathogens isolated

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from intraabdominal (IAI) and urinary tract infections (UTI), and are more prevalent in patients with

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chronic underlying conditions and in healthcare-associated infections, such as those associated with

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recent urinary tract instrumentation or in-dwelling catheters [1,3-5].

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Infections caused by P. aeruginosa are often difficult to treat. The species typically shows high levels of

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antimicrobial resistance due to increased expression of β-lactamases and multiple efflux pumps,

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decreased expression of porins, modifications of antimicrobial targets (penicillin-binding proteins),

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and/or acquisition of extended-spectrum β-lactamases (ESBLs) and carbapenemases [6]. Antimicrobial

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resistance typically varies across different patient groups and settings. For example, resistance--

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especially due to ESBLs and carbapenemases--is higher in ICUs than other wards, increasing the risk to

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patients of acquiring resistant isolates [7,8]. Studies have also reported higher resistance rates in

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hospital-associated than community-associated infections, in elderly than younger patients, and in male

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than female patients with UTI [9,10]. Most studies have examined Enterobacteriaceae, but knowledge of

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the risk of infection with resistant P. aeruginosa isolates would also allow more discriminatory

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prescribing of empiric broad-spectrum antipseudomonal antimicrobials. Studies on P. aeruginosa in ICUs

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illustrate that therapeutic options may be severely limited in this setting [11], indicating a need for

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additions to the therapeutic armamentarium. Ceftolozane-tazobactam is an antipseudomonal

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cephalosporin/β-lactamase inhibitor that has been approved in the United States and over 60 countries

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worldwide for the treatment of complicated IAI and UTI and is being evaluated for other conditions

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including nosocomial pneumonia [12]. Ceftolozane has potent activity against P. aeruginosa, including

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isolates resistant to carbapenems, piperacillin-tazobactam, or ceftazidime, due to its ability to evade

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several resistance mechanisms, including efflux pumps, reduced uptake through porins, modification of

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PBPs, and derepressed AmpCs [6,13]. The addition of tazobactam broadens the spectrum of ceftolozane

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to include many ESBL producers and some anaerobes, thus offering clinicians an alternative option for

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empirical treatment of serious gram-negative infections [6].

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The objective of this study was two-fold: 1) to describe the epidemiology of P. aeruginosa and its

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susceptibility to commonly used antimicrobial agents across different risk strata, and 2) to examine the

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activity of ceftolozane-tazobactam against P. aeruginosa and resistant phenotypes found in these risk

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strata, using recent clinical isolates collected as part of the Study for Monitoring Antimicrobial

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Resistance Trends (SMART) in the United States.

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2. Materials and methods

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2.1. Clinical isolates

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From 2016 to 2017, 25 hospitals in 18 states of the United States participated in the SMART global

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surveillance program and were requested to collect up to 250 consecutive aerobic or facultatively

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anaerobic gram-negative bacilli per year (100 isolates from lower respiratory tract infections per year,

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100 isolates from intra-abdominal infections in 2016 and 75 isolates in 2017, and 50 isolates from

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urinary tract infections in 2016 and 75 isolates in 2017). Only one isolate per patient per gram-negative

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species was permitted per year. Isolates were determined to be clinically significant by algorithms in

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place at participating laboratories and were accepted without regard to their antimicrobial susceptibility

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profile. A total of 9,964 isolates of gram-negative bacilli was collected, of which 1,887 were P.

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aeruginosa. Among the P. aeruginosa isolates, 80 isolates came from patients who were in the

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emergency department at the time of specimen collection and for 264 isolates no patient location was

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specified. Both groups of isolates were not included in the analysis comparing isolates from ICU and

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non-ICU wards. For 364 P. aeruginosa isolates, length of hospital stay at the time of specimen collection

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was not specified, and those isolates were not included in the comparison of isolates collected ≥48

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versus <48 hours post-admission. For 3 isolates, patient age was not specified, and these isolates were

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not included in the comparison of age groups. All isolates were transported to International Health

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Management Associates, Inc. (IHMA; Schaumburg, IL, USA) which served as the central testing

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laboratory for the SMART global surveillance program. All isolates received by IHMA were re-identified

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using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (Bruker

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Daltonics, Billerica, MA, USA).

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2.2 Antimicrobial susceptibility testing

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MICs were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth

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microdilution method with custom-made dehydrated panels manufactured by TREK Diagnostic Systems

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(Thermo Fisher Scientific, Oakwood Village, OH, USA) [14,15]. MICs were interpreted as susceptible,

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intermediate, or resistant using 2018 CLSI breakpoints [15].

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Fisher’s exact test was used to compare antimicrobial susceptibility rates of isolates from patients in ICU

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versus non-ICU hospital wards, isolates collected ≥48 versus <48 hours post-admission, and isolates from

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younger (<65 years of age) versus older (≥65 years) patients. P values <0.05 were considered statistically

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significant.

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3. Results

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Among all gram-negative bacilli collected in 2016-2017 in the United States, the proportion of P.

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aeruginosa was 18.9% (1,887/9,964), with a slightly higher percentage among isolates from ICU wards

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(21.4%) than non-ICU wards (18.2%), among isolates from patients with specimen collection ≥48 hours

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post-admission (20.4%) than <48 hours (16.6%), and among isolates from patients ≥65 years of age

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(19.7%) than <65 years (18.5%) (Supplemental Table 1). Comparing specimen sources, a higher

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proportion of P. aeruginosa isolates was found among RTI isolates (31.3%, 1,270/4,059) than among IAI

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(11.4%, 340/2,985) or UTI isolates (9.2%, 261/2,851) (Supplemental Table 2). Supplemental Tables 1 and

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2 also provide details on the other gram-negative species collected.

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Among P. aeruginosa isolates from all specimen sources, ceftolozane-tazobactam showed the highest

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susceptibility of the studied agents (>91% in all strata) with small differences between strata (Figure 1).

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Statistically significant differences were found between ward types and between age groups, but

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ceftolozane-tazobactam susceptibility of ICU isolates and isolates from younger patients was only 2-4

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percentage points lower than isolates from non-ICU wards and older patients. The MIC50 value was 1

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µg/ml across all strata, and the MIC90 value was 4 µg/ml in all strata except the isolates collected <48

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hours after admission (2 µg/ml, Supplemental Table 3). Susceptibility of P. aeruginosa overall to the

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comparator agents was ≤77%. The differences in susceptibility rates between the strata were larger for

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the β-lactam comparators than for ceftolozane-tazobactam, and all were statistically significant except

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the comparison between age groups, which was only significant for piperacillin-tazobactam (p<0.05).

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MIC50 and MIC50 values for the comparator agents are shown in Supplemental Table 3. Among the β-

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lactam-nonsusceptible subsets, ceftolozane-tazobactam maintained activity against 76-88% of isolates

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in all strata, whereas susceptibility to the comparators was 6%-54% (Table 1).

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Compared to the results for the complete isolate collection, analyses restricted to RTI showed

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susceptibility of P. aeruginosa isolates to ceftazidime, meropenem, and piperacillin-tazobactam that was

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3 to 12 percentage points lower than those for IAI and UTI isolates (Table 2). Ceftolozane-tazobactam

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maintained activity against >91% of RTI isolates in all risk strata, with susceptibility to the comparator

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agents 16-30 percentage points lower. Susceptibility was slightly lower in ICU than non-ICU isolates, in

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isolates collected ≥48 hours than those collected <48 hours post-admission, and in younger than older

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patients. Not all of these differences were statistically significant, and again they were much smaller

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than those seen for the β-lactam comparators, which showed especially low susceptibility rates in ICUs.

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Against the β-lactam-nonsusceptible subsets of RTI isolates, ceftolozane-tazobactam maintained activity

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against 75-89% of isolates in all strata, with susceptibility to the comparator agents 28-80 percentage

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points lower. Similarly, ceftolozane-tazobactam maintained activity against >90% of isolates from IAI

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and UTI in all strata, with susceptibility to the comparators 8-46 percentage points lower (Table 2).

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Sample sizes were too small to allow for analysis of β-lactam-nonsusceptible subsets among IAI and UTI

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isolates.

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An analysis of susceptibility across the 25 participating hospitals showed some variability, with

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susceptibility to ceftolozane-tazobactam ranging from 88.9% to 100% and greater variability for the

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comparator agents (Supplemental Table 4). However, sample sizes for several individual laboratories

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were small, with 6 sites submitting fewer than 50 isolates.

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4. Discussion

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P. aeruginosa is a species with a remarkable capacity to develop resistance to antimicrobial agents

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through numerous and evolving mechanisms [16]. In the current study, overall in vitro susceptibility

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rates of P. aeruginosa to commonly used agents ranged from 69% for levofloxacin to 77% for

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ceftazidime and meropenem. Antimicrobial resistance of P. aeruginosa varied according to infection

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source, ward type, length of hospital stay at time of specimen collection, and patient age. Similar to a

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recent surveillance study by Sader et al., susceptibility to multiple antimicrobial agents was lower among

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isolates from patients with RTI than those with IAI or UTI [17]. Among all isolates combined, as well as in

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analyses stratified by specimen source, susceptibility was reduced among isolates from ICUs compared

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to non-ICU wards, a finding supported by other surveillance studies [7,8]. Similarly, lower susceptibility

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was seen in isolates collected ≥48 hours after hospital admission compared to those collected within 48

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hours of admission. Knowing that P. aeruginosa is typically found only in healthcare-associated

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infections [1,2], it is possible that many of the patients with isolates collected <48 hours after hospital

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admission had some prior contact with the healthcare system; therefore it is interesting that resistance

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to several β-lactams was nevertheless significantly lower in patients who had been in the hospital <48

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hours when the specimen was collected compared to those who had been in the hospital for longer and

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had therefore probably acquired the infection during the current hospital stay.

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Not only were P. aeruginosa isolates more resistant among ICU isolates, among isolates collected ≥48

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hours after hospital admission, and among isolates from patients with RTI, but the prevalence of this

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species was also higher in those strata, thus compounding the risk of acquiring an antimicrobial-resistant

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infection with its associated treatment challenges. Interestingly, this pattern did not apply to the age

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group comparison, where P. aeruginosa was more prevalent in older patients but resistance was slightly

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higher in younger patients (aged <65 years). Higher resistance in the younger age group was found both

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among RTI and UTI isolates, and the difference between age groups was more pronounced when only

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adults aged 18-64 were compared to the older adults (i.e., pediatric isolates were excluded, data not

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shown). This resistance pattern is different from the findings of other studies examining antimicrobial

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susceptibility across age groups, which reported higher levels of antimicrobial resistance in pathogens

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from older patients [9,10,18]; however, those reports focused mostly on E. coli from UTI. Our finding

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was similar to the results of an international study of nosocomial pneumonia that reported decreasing

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age as an independent predictor of multidrug-resistance of P. aeruginosa [19] and a Canadian study that

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found higher resistance in P. aeruginosa isolates from multiple specimen sources in adults aged 19-64

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than in older adults [18].

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The differences in susceptibility between risk strata were smaller for ceftolozane-tazobactam than for

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the β-lactam comparators, and it maintained in vitro activity against >90% of P. aeruginosa isolates from

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each subset. Among isolates nonsusceptible to meropenem, ceftolozane-tazobactam susceptibility

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rates were ≥80% in all strata except ICUs (77.9%), and rates ranged from 75.5% to 85.9% against the

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ceftazidime- and piperacillin-tazobactam-nonsusceptible subsets. The activity of ceftolozane-

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tazobactam against P. aeruginosa overall was 94.7%, ranging from 94% in RTI and IAI isolates to 98.5% in

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UTI isolates. These results were slightly higher than the susceptibility of 91.7% reported in a study of P.

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aeruginosa isolates from IAI and UTI collected in Europe in 2012-2015 as part of the PACTS (Program to

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Assess Ceftolozane-Tazobactam Susceptibility) antimicrobial surveillance program [5] and were slightly

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lower than the susceptibility of 97.0% reported in a PACTS study of P. aeruginosa isolates from various

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infection sources, including RTI, IAI, and UTI, collected in the United States in 2012-2015 [20].

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Ceftolozane-tazobactam is able to evade the typical resistance mechanisms in P. aeruginosa and has

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been reported to show a low propensity for selection of resistant P. aeruginosa strains [6]. Furthermore,

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development of resistance of P. aeruginosa to ceftolozane-tazobactam does not appear to be driven by

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a single-step mutation, with in vitro resistance developing much slower than for other antipseudomonal

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agents and at a high biological cost [6,16]. In fact, the mutations in isolates with high-level ceftolozane-

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tazobactam resistance showed increased cephalosporin resistance but reduced resistance to penicillins

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and carbapenems [16]. Therefore, ceftolozane-tazobactam may be a valuable option in the treatment of

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infections with P. aeruginosa, not only as a carbapenem-sparing option but also to minimize the risk of

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self- and cross-resistance [16]. Nevertheless, continued surveillance is important to monitor resistance

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to ceftolozane-tazobactam and other antipseudomonal agents.

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In conclusion, in vitro antimicrobial susceptibility of recent clinical P. aeruginosa isolates collected in the

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United States to commonly used β-lactams was <80% and varied according to ward type, length of

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hospital stay at time of specimen collection, patient age, and infection source. Knowledge of such

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resistance patterns can help clinicians select appropriate agents for empiric therapy. Ceftolozane-

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tazobactam maintained in vitro activity against >90% of isolates, regardless of risk stratum or specimen

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source, and represents a promising new treatment option even in strata in which the risk of infection

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with β-lactam-nonsusceptible P. aeruginosa appeared higher.

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Declarations

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Funding: Funding for this research was provided by by Merck Sharp & Dohme Corp., a subsidiary of

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Merck & Co., Inc., Kenilworth, NJ, USA, which also included compensation for services in relation to

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preparing this manuscript.

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Competing Interests: SHL, DJH, and DFS work for International Health Management Associates, Inc.,

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which receives funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth,

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NJ, USA for the SMART surveillance program. KY and MRM are employees of Merck Sharp & Dohme

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Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and own stock and options in the company.

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The IHMA authors do not have personal financial interests in the sponsor of this manuscript (Merck

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Sharp & Dohme Corp.).

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Ethical Approval: Not required.

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The authors thank all the participants in the SMART program for their continuing contributions to its

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success.

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Monitoring (INFORM) Surveillance Program, 2015–2016. Diagn Microbiol Infect Dis 2018; 92(1):

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69-74. doi:https://doi.org/10.1016/j.diagmicrobio.2018.04.012 [18]

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Adam HJ, Baxter MR, Davidson RJ, Rubinstein E, Fanella S, Karlowsky JA et al. Comparison of

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pathogens and their antimicrobial resistance patterns in paediatric, adult and elderly patients in

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Canadian hospitals. J Antimicrob Chemother 2013; 68(suppl_1): i31-i37. doi:10.1093/jac/dkt024

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[19]

Micek ST, Wunderink RG, Kollef MH, Chen C, Rello J, Chastre J et al. An international multicenter

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retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multidrug

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resistance. Critical Care 2015; 19(1): 219. doi:10.1186/s13054-015-0926-5

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Shortridge D, Castanheira M, Pfaller MA, Flamm RK. Ceftolozane-Tazobactam Activity against Pseudomonas aeruginosa Clinical Isolates from U.S. Hospitals: Report from the PACTS

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Antimicrobial Surveillance Program, 2012 to 2015. Antimicrob Agents Chemother 2017; 61(7):

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e00465-00417. doi:10.1128/AAC.00465-17

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Figure Legend

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Figure 1. Susceptibility of P. aeruginosa from all specimen sources in different risk strata and overall. The

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total number of collected isolates is shown in the legend.

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a

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* Statistically significant difference between ICU/non-ICU, specimen collection ≥48 hours/<48 hours

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post-admission, or age groups (p<0.05, Fisher's exact test)

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ICU, intensive care unit; Non-ICU, non-ICU hospital wards

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Length of hospital stay at time of specimen collection

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Table 1. Susceptibility of resistant phenotypes of P. aeruginosa from all specimen sources combined

<65 years 276 76.1 47.1 7.6 44.6 261 80.1 44.1 29.9 32.2 355 81.1 28.2 48.5 43.7

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ICU 159 75.5 45.3 7.6 44.0 145 77.9 40.0 29.0 33.1 188 78.7 21.8 45.2 39.4

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All 438 78.5 48.2 7.1 45.2 435 83.2 47.8 33.8 34.9 562 82.9 27.6 48.8 44.3

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Phenotype/Drug Ceftazidime-NS (n) Ceftolozane-tazobactam Meropenem Piperacillin-tazobactam Levofloxacin Meropenem-NS (n) Ceftolozane-tazobactam Ceftazidime Piperacillin-tazobactam Levofloxacin Piperacillin-tazobactam-NS (n) Ceftolozane-tazobactam Ceftazidime Meropenem Levofloxacin

% Susceptible a a Non-ICU ≥48 hours <48 hours 201 204 147 79.6 78.4 81.0 49.3 47.1 48.3 7.5 6.9 8.8 43.3 47.6 40.1 209 205 152 86.1 83.9 86.8 51.2* 47.3 50.0 37.3 32.7 38.8 33.5 40.5 27.0* 268 260 185 84.3 82.7 84.9 30.6* 26.9 27.6 51.1 46.9 49.7 46.6 48.1 37.3*

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a

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* Statistically significant difference between ICU/non-ICU, specimen collection ≥48 hours/<48 hours post-admission, or age

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groups (p<0.05, Fisher's exact test)

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ICU, intensive care unit; Non-ICU, non-ICU hospital wards; NS, nonsusceptible

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Length of hospital stay at time of specimen collection

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≥65 years 161 82.6 50.3 6.2 46.6 172 87.8* 53.5 39.5* 39.5 206 85.9 26.7 49.5 45.6

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Table 2. Susceptibility of P. aeruginosa and resistant phenotypesa

<65 years 766 92.6 72.6 74.0 66.8 65.7 210 74.8 44.3 7.6 41.9 199 78.4 41.2 31.2 32.7

≥65 years 502 96.2* 77.7* 75.5 71.1 71.5* 112 84.8* 51.8 4.5 53.6* 123 88.6* 56.1* 41.5 44.7*

254 78.7 23.6 46.1 42.1 215 94.9 80.0 84.7 74.4 81.4 126 98.4 82.5 78.6 65.9 69.1

145 87.6* 26.2 50.3 51.0 124 92.7 75.0 74.2* 71.8 61.3* 135 98.5 86.7 87.4 80.7* 67.4

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161 78.3 20.5 47.2 42.2 53 90.6 69.8 67.9 64.2 66.0 24 100 83.3 83.3 70.8 54.2

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399 82.0 24.6 47.6 45.4 340 94.1 77.9 80.6 73.2 73.8 261 98.5 84.7 83.1 73.6 68.2

% Susceptible a a Non-ICU ≥48 hours <48 hours 604 538 472 95.5* 94.1 94.5 79.5* 72.1 78.2* 75.7 71.2 76.7 73.2* 65.1 74.4* 65.9 69.3 65.7 124 150 103 79.8 80.0 77.7 43.6 47.3 42.7 7.3 5.3 10.7 42.7 48.7 37.9 147 155 110 86.4 84.5 84.6 52.4 49.0 46.4 41.5 35.5 39.1 35.4 42.6 29.1*

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ICU 435 91.5 68.3 71.7 63.0 69.9 138 75.4 47.1 7.3 45.7 123 77.2 40.7 30.9 35.0

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Piperacillin-tazobactam-NS (n) Ceftolozane-tazobactam Ceftazidime Meropenem Levofloxacin All P. aeruginosa from IAI (n) Ceftolozane-tazobactam Ceftazidime Meropenem Piperacillin-tazobactam Levofloxacin All P. aeruginosa from UTI (n) Ceftolozane-tazobactam Ceftazidime Meropenem Piperacillin-tazobactam Levofloxacin

All 1270 94.0 74.7 74.6 68.6 68.0 322 78.3 46.9 6.5 46.0 323 82.4 47.1 35.3 37.2

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Organism/Phenotype/Drug All P. aeruginosa from RTI (n) Ceftolozane-tazobactam Ceftazidime Meropenem Piperacillin-tazobactam Levofloxacin Ceftazidime-NS (n) Ceftolozane-tazobactam Meropenem Piperacillin-tazobactam Levofloxacin Meropenem-NS (n) Ceftolozane-tazobactam Ceftazidime Piperacillin-tazobactam Levofloxacin

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162 84.0 29.0 46.9 46.3 239 94.6 79.1 85.4* 74.1 74.5 175 98.3 84.6 85.1 76.0 73.1

188 83.5 24.5 46.8 49.5 140 91.4 72.1 74.3 65.7 70.7 69 97.1 78.3 81.2 66.7 72.5

121 81.0 24.0 44.6 34.7* 142 97.9* 83.8* 89.4* 80.3* 77.5 151 98.7 86.8 82.8 77.5 68.9

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a

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* Statistically significant difference between ICU/non-ICU, specimen collection ≥48 hours/<48 hours post-admission, or age

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groups (p<0.05, Fisher's exact test)

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ICU, intensive care unit; Non-ICU, non-ICU hospital wards; NS, nonsusceptible

Length of hospital stay at time of specimen collection

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Activity of Ceftolozane-Tazobactam and Comparators against Pseudomonas aeruginosa from Patients in Different Risk Strata -- SMART United States 2016-2017

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Highlights

Infections caused by Pseudomonas aeruginosa (PA) are often difficult to treat



In the US, prevalence of PA and susceptibility to β-lactams differed by risk strata



Prevalence of PA was higher and susceptibility lower in ICU than in non-ICU wards



Susceptibility was lower in isolates from younger patients, and from respiratory infections



Ceftolozane-tazobactam maintained activity against >90% of PA in all risk strata

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